Project Summary/Abstract Glaucoma is one of the leading causes of blindness worldwide, yet we are still trying to develop a fundamental understanding of the pathophysiologic mechanisms underlying the retinal ganglion cell (RGC) loss. We know that glaucoma damages axons of RGCs at the level of the lamina cribrosa. With the increasing interest in understanding the ocular biomechanics of the optic nerve head (ONH) and the role of translaminar pressure differences in the development of glaucoma, it is imperative that researchers have access to animal models that most closely represent the normal human anatomy and develop key pathologic features of the human disease. Further, these models are instrumental in helping translate basic science discoveries, such as novel pharmacological therapeutics, from the in vitro, pre-clinical stage into human clinical trials. Two of the most commonly used animal models of glaucoma, non-human primates and rodents, each have significant limitations or barriers to their use. Thus, there is a critical need for additional novel animal models of glaucoma. The tree shrew (Tupaia belangeri) is a small mammal closely related to primates. It has a robust connective tissue lamina with horizontally oriented laminar beams that insert into the peripapillary sclera and are thus, load-bearing. We hypothesize that the tree shrew model of glaucoma is an ideal bridge between the non-human primate and rodent models currently being used. Our primary goal is to optimize and validate the tree shrew model of glaucoma via the following: Specific Aim 1: Optimize the methods for inducing elevation of intraocular pressure (IOP) and achieve a sustained, moderate level of IOP elevation that results in an optic neuropathy with isolated retinal nerve fiber layer loss and laminar deformations consistent with glaucomatous ONH cupping. After occluding variable amounts of anterior chamber angle with magnetic microspheres, we will obtain IOP measures, in-vivo optical coherence tomography (OCT) images, and complete ONH histomorphometric analysis along with axon counts to determine which degree of occlusion provides the most optimal, moderate IOP increase that is sustainable over time. Specific Aim 2: Complete a longitudinal study correlating IOP, RNFL thinning, and posterior laminar bowing to the axon counts and ONH histomorphometry in early, intermediate, and late phases of experimental glaucoma in tree shrews. IOP measures and in vivo OCT imaging will be completed. In addition, histomorphometric analysis and reconstruction of the ONH will be completed at 1, 3, and 6 months for longitudinal analysis of the pathological features in this model and allow for comparison to the human condition. We believe the tree shrew model of glaucoma has the potential to help researchers accelerate our understanding of glaucoma pathophysiology and assist in the development of novel treatment options for patients with glaucoma, thus validation of this model is the next critical step.